Grand RoundsGrand RoundsEthambutol ToxicityEthambutol Toxicity

Mark Sherman MDMark Sherman MD

University of LouisvilleUniversity of Louisville

Department of Ophthalmology and Visual Department of Ophthalmology and Visual SciencesSciences

11/21/201411/21/2014

SubjectiveSubjectiveCC:CC: Decreased vision OU x 4 months Decreased vision OU x 4 months

HPIHPI: 77 year old white female referred to the neuro-: 77 year old white female referred to the neuro-ophthalmology clinic with complaint of progressively worse ophthalmology clinic with complaint of progressively worse decreased vision OU for the past four months. No other decreased vision OU for the past four months. No other complaints.complaints.Patient had been 20/20 OU after cataract surgery 12 months Patient had been 20/20 OU after cataract surgery 12 months prior prior

POHPOH: PCIOL OU, POAG on Timolol BID OU: PCIOL OU, POAG on Timolol BID OU

PMH:PMH: Arthritis, Colon CA s/p resection in 2012, Pneumonia Arthritis, Colon CA s/p resection in 2012, Pneumonia (around time of initial visual decline)(around time of initial visual decline)

Meds:Meds: Aspirin, Ethambutol, Clarithromycin Aspirin, Ethambutol, Clarithromycin

ExamExam ODOD OSOS

BCVABCVA: CF @1’: CF @1’ CF @3’ CF @3’

Pupils:Pupils: 5 53 3 5 53 3

No APDNo APD

IOPIOP:: 16 16 14 14

EOM:EOM: Full OU Full OU

CVF:CVF: Constricted OU Constricted OU

SLE:SLE: ODOD OSOS

L/LL/L WNLWNL WNLWNL ConjunctivaConjunctiva WNLWNL WNLWNL KK WNLWNL WNLWNL ACAC WNL WNL WNLWNL I/LI/L PCIOL PCIOL PCIOLPCIOL

DFE:DFE: c/d: 0.4 OU +PPA; MVP WNL OUc/d: 0.4 OU +PPA; MVP WNL OU

ExamExam

HVF 24-2HVF 24-2

Optic Nerve OCTOptic Nerve OCT

OCTOCT

MRI Brain/OrbitsMRI Brain/Orbits

Impression:Impression:1.1.No acute intracranial findingsNo acute intracranial findings2.2.Nonspecific findings likely secondary Nonspecific findings likely secondary to chronic small vessel diseaseto chronic small vessel disease

Assessment/PlanAssessment/Plan

Assessment:Assessment: 77 year old female with 77 year old female with significantly decreased vision OU x 4 significantly decreased vision OU x 4 months with constricted visual fields OU months with constricted visual fields OU and otherwise normal exam and imagingand otherwise normal exam and imaging

Dx:Dx: Toxic optic neuropathy Toxic optic neuropathy secondary secondary

to ethambutolto ethambutol

Plan:Plan: Discontinue ethambutolDiscontinue ethambutol

Toxic Optic NeuropathyToxic Optic Neuropathy

Characterized byCharacterized by Gradual, progressive bilateral vision lossGradual, progressive bilateral vision loss PainlessPainless Central vision lossCentral vision loss Decreased color visionDecreased color vision Absent APD due to symmetric visual lossAbsent APD due to symmetric visual loss

Ophthalmic exam findings may be minimal Ophthalmic exam findings may be minimal or subtleor subtle Optic atrophy can develop if the cause is not Optic atrophy can develop if the cause is not

correctedcorrected Can present with mild to moderate disc edemaCan present with mild to moderate disc edema

Toxic Optic NeuropathyToxic Optic Neuropathy

Common etiologies:Common etiologies: Ethambutol (occurs in up to 6% of patients)Ethambutol (occurs in up to 6% of patients) AmiodaroneAmiodarone IsoniazidIsoniazid ChloramphenicolChloramphenicol Antineoplastic agents: cisplatin and vincristineAntineoplastic agents: cisplatin and vincristine B12, thiamine, or folate deficiencyB12, thiamine, or folate deficiency MethanolMethanol Ethylene glycolEthylene glycol

Toxic Optic NeuropathyToxic Optic Neuropathy

Diagnosis of exclusion made with a Diagnosis of exclusion made with a detailed history and work up to rule out detailed history and work up to rule out other etiologiesother etiologies

Differential diagnosis includes subtle Differential diagnosis includes subtle maculopathies and hereditary, maculopathies and hereditary, compressive, demyelinating, or infiltrative compressive, demyelinating, or infiltrative optic neuropathiesoptic neuropathies

Neuroimaging is routinely performed to Neuroimaging is routinely performed to rule out any compressive etiologyrule out any compressive etiology

Toxic Optic NeuropathyToxic Optic Neuropathy Treatment is aimed at stopping the Treatment is aimed at stopping the

inciting medication, substance abuse, or inciting medication, substance abuse, or replacement of dietary deficienciesreplacement of dietary deficiencies

Prognosis for visual recovery is good Prognosis for visual recovery is good unless optic atrophy has occurredunless optic atrophy has occurred

Visual recovery is slow, usually 3-9 Visual recovery is slow, usually 3-9 months months

Patients with ethambutol toxicity will Patients with ethambutol toxicity will often have a worsening of vision and often have a worsening of vision and visual fields for several months after visual fields for several months after stopping the medication before stopping the medication before improvement beginsimprovement begins

The protective effects of caffeic acid phenethyl The protective effects of caffeic acid phenethyl ester (CAPE) in isoniazid and ethambutol-induced ester (CAPE) in isoniazid and ethambutol-induced

ocular toxicity in ratsocular toxicity in rats CAPE: a natural phenolic compound found CAPE: a natural phenolic compound found

in plants used in a variety of cancer in plants used in a variety of cancer treatment studies for its anti-treatment studies for its anti-inflammatory effectsinflammatory effects

Study of 8 groups, each including 10 rats:Study of 8 groups, each including 10 rats: Control, isoniazid alone, ethambutol alone, CAPE alone, Control, isoniazid alone, ethambutol alone, CAPE alone,

isoniazid +CAPE, ethambutol +CAPE, isoniazid with isoniazid +CAPE, ethambutol +CAPE, isoniazid with ethambutol, isoniazid with ethambutol and CAPEethambutol, isoniazid with ethambutol and CAPE

After 30 days the eyes underwent After 30 days the eyes underwent histopatholoic evaluation and retinal histopatholoic evaluation and retinal ganglion cell countganglion cell count Isoniazide alone, ethambutol alone, and ethambutol Isoniazide alone, ethambutol alone, and ethambutol

with isoniazid groups all had significantly decreased with isoniazid groups all had significantly decreased retinal ganglion cell counts compared to the groups retinal ganglion cell counts compared to the groups that had CAPEthat had CAPE

ReferencesReferences BCSC: Neuro-Ophthalmology. BCSC: Neuro-Ophthalmology. Toxic/Nutrinitional Toxic/Nutrinitional

optic neuropathy.optic neuropathy. Pgs: 154-155 Pgs: 154-155 Grzybowski A, Zulsdorff, et al. Toxic optic Grzybowski A, Zulsdorff, et al. Toxic optic

neuropathies: An updated review. neuropathies: An updated review. Acta Acta Opthahlmol.Opthahlmol. 2014 August. 2014 August.

Kumar A, Sandramouli S, Verma L, et al. Ocular Kumar A, Sandramouli S, Verma L, et al. Ocular ethambutol toxicity: is it reversible? ethambutol toxicity: is it reversible? J Clin Neuro-J Clin Neuro-Ophthalmol.Ophthalmol.1993; 13(1)15-171993; 13(1)15-17

Mascaluso DC, Shults ET, et al. Features of Mascaluso DC, Shults ET, et al. Features of Amiodarone-induced optic neuropathy. Amiodarone-induced optic neuropathy. Am J Am J Ophathalmol.Ophathalmol. 1999;127(5):610-12 1999;127(5):610-12

Sahin A, Kursat, et al. The protective effects of Sahin A, Kursat, et al. The protective effects of caffeic acid phenethyl ester in isoniazid and caffeic acid phenethyl ester in isoniazid and ethambutol-induced ocular toxicity in rats. ethambutol-induced ocular toxicity in rats. Cutan Cutan Ocul ToxicityOcul Toxicity. 2013 Sep;32(3)228-33.. 2013 Sep;32(3)228-33.